Narcolepsy, a disorder which affects approximately 1 in 2,000 individuals, is characterized by daytime sleepiness, sleep fragmentation, and symptoms of abnormal rapid eye movement (REM) sleep that include cataplexy (loss of muscle tone), sleep paralysis, and hypnagogic hallucinations (Aldrich, M. S., Neurology 42:34-43 (1992); Siegel, J. M., Cell 98:409-412 (1999)). In humans, susceptibility to narcolepsy has been associated with a specific human leukocyte antigen (HLA) alleles, including DQB1*0602 (Mignot, E., Neurology 50:S16-22 (1998); Kadotani, H. et al., Genome Res. 8:427-434 (1998); Faraco, J. et al., J Hered. 90:129-132 (1999)); however, attempts to verify narcolepsy as an autoimmune disorder have failed (Mignot, E. et al., Adv. Neuroimmunol. 5:23-37 (1995); Mignot, E., Curr. Opin. Pulm. Med. 2:482-487 (1996)). In a canine model of narcolepsy, the disorder is transmitted as an autosomal recessive trait, canarc-1 (Foutz, A.S. et al., Sleep 1:413-421 91979); Baker, T. L. and Dement, W. C., Brain Mechanisms of Sleep (D. J. McGinty et al., eds., New York: Raven Press, pp. 199-233 (1985)). The possibility of linkage between canare-1 and the canine major histocompatibility complex has been excluded (Mignot, E. et al., Proc. Natl. Acad. Sci. USA 88:3475-3478 (1991)).
A mutation in the hypocretin (orexin) receptor 2 gene in canines has been identified in narcolepsy (Lin, L. et al., Cell 98:365-376 (1999)); Hypocrexins/orexins (orexin-A and -B) are neuropeptides associated with regulation of food consumption (de Lecea, L., et al., Proc. natl. Acad. Sci. USA 95:322-327 (1998); Sakurai, T. et al., Cell 92:573-585 (1998)) as well as other possible functions (Peyron, C. et al., J Neurosci. 18:9996-10015 (1998)). Human cDNA of receptors for orexins have been cloned (Sakurai, T. et al., Cell 92:573-585 (1998)), however, full human genes for the orexin receptors have not yet been identified.
Diagnosis of narcolepsy is difficult, as it is necessary to distinguish narcolepsy from other conditions such as chronic fatigue syndrome or other sleep disorders (Ambrogetti, A. and Olson, L. C., Med. J Aust. 160:426-429 (1994); Aldrich, M. S., Neurology 50:S2-7 (1998)). Methods of diagnosing narcolepsy based on specific criteria would facilitate identification of the disease, reduce the time and expense associated with diagnosis, and expedite commencement of treatment.
As described herein, a full gene for the human hypocretin (orexin) receptor 2 (HCRTR2) has been identified. The sequence of the HCRTR2 gene as described herein is shown in FIG. 1 (SEQ ID NO: 1). Accordingly, this invention pertains to an isolated nucleic acid molecule containing the HCRTR2 gene. The invention also relates to DNA constructs comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence, and to recombinant host cells, such as bacterial cells, fingal cells, plant cells, insect cells and mammalian cells, comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence. The invention also pertains to methods of diagnosing narcolepsy in an individual. The methods include detecting the presence of a mutation in the HCRTR2 gene. The invention additionally pertains to pharmaceutical compositions comprising the HCRTR2 nucleic acids of the invention. The invention further pertains to methods of treating narcolepsy, by administering HCRTR2 nucleic acids of the invention or compositions comprising the HCRTR2 nucleic acids. The methods of the invention allow the accurate diagnosis of narcolepsy and reduce the need for time-consuming and expensive sleep laboratory assessments.